Cocaine addiction: Role for glutamate, glia and chemokine

Abstract

Aims: The aim of the study is to investigate the effect of novel activators of glutamate transporter (GLT-1), ceftriaxone (CTX) and clavulanic acid (CLAV), on drug taking and seeking behavior. In addition, glial cell activity after cocaine exposure and during short and long-termwithdrawal has been examined. Furthermore, possible involvement of chemokine receptor, CXCR4, in cocaine reward was examined. Methods: The effect of CTX and CLAV was tested in mouse intravenous self-administration model. Acquisition of selfadministration under fixed-ratio (FR) schedule of reinforcement was used as a measure of drug-taking behavior, and progressive ratio (PR) schedule of reinforcement was used to assess drugseeking behavior. In a separate study, rats were injected with cocaine (15mg/kg, i.p.) for 7 consecutive days, and glial cell activitywas investigated using immuno-fluorescencemicroscopy at 2h, 2, 10 and 30 days after last injection. Effect of AMD3100, a CXCR4 antagonist, on development of cocaine conditioned place preference was tested. Results: CTX and CLAV pretreatment decreased cocaine intake in mice maintained under the PR of reinforcement. However only the CTX not CLAV pre-treatment was able to decrease acquisition of self-administration in mice under FR schedule of reinforcement. There was a significant increase of astrocytic activation in nucleus accumbens of rats withdrawn from cocaine for 30 days. AMD3100 attenuated development of cocaine conditioned place preference. Conclusions: GLT-1 activators are able to decrease reinforcing strength of cocaine by increasing the extracellular glutamate reuptake. Astrocyte activity is increased in nucleus accumbens of rats in long-term cocaine withdrawal. Attenuation of cocaine conditioned place preference byAMD3100 suggests a role for chemokine receptor in drug reward. Financial Support: T32 DA 07237 P30 DA013429R21 DA043718.